In mammals, the unique tight junctions of urinary bladder surface epithelial cells are the fundamental mechanism by which the urinary bladder maintains impermeability. The glycosaminoglycan layer on the luminal surface of the urinary bladder wall may be an important defense mechanism for protecting the transitional epithelium from urinary irritants (Chelsky, M. et al. 1994., Journal of Urology, 151:346). This glycosaminoglycan layer consists of mucopolysaccharides attached to a core protein that, in turn, is bound to a central hyaluronic acid string. This highly viscous, highly hydrophilic glycosaminoglycan layer may protect the transitional epithelium of the urinary bladder from irritants in the urine including, but not limited to, pathogens, microcrystals, proteins, calcium and carcinogens (Nickel, J. C. et al. 1993. Journal of Urology, 149:716). This glycosaminoglycan layer also may prevent small, uncharged molecules such as urea from diffusing to and across the transitional cell epithelium. Thus, the glycosaminoglycan layer lining the urinary bladder may act as a barrier between the environment within the lumen of the urinary bladder and the transitional epithelium of the urinary bladder, and may protect this transitional epithelium from inflammation, infection, trauma, stone formation and carcinogenesis.
Cystitis is an inflammation of the urinary bladder and associated structures for which there is no universal effective treatment program (Fleischmann, J. D. et al. 1991. Journal of Urology, 146:1235). Symptoms resulting from cystitis include, but are not limited to, urgency for urination, increased frequency of urination and suprapubic pain usually relieved by voiding. Other symptoms can include, but are not limited to, arthritis, spastic colon, low grade fever and irritability. Mammals with cystitis can be significantly disabled, and mammals with advanced cystitis can require major surgery in order to function.
Cystitis can result from, among other causes, infection, trauma, allergy, malignancy, uroliths, acute causes and undetermined causes. Infection associated cystitis includes, but is not limited to, inflammation of the urinary bladder and associated structures associated with bacterial, fungal, yeast, viral and parasitic causes. Trauma associated cystitis includes, but is not limited to, inflammation of the urinary bladder and associated structures associated with mechanical, chemical and surgical causes. Mechanical causes include, but are not limited to, cystoscopy, traumatic fibrosis, ultrasound, radiation therapy, catheterization and spinal cord damage. Surgical causes include, but are not limited to, tumor resection, cystotomy, urinary bladder ablation, urethrostomy, and cystocentesis. Allergy associated cystitis includes, but is not limited to, inflammation of the urinary bladder and associated structures associated with hypersensitivity reactions and drug reactions. Acute causes of cystitis includes but are not limited to, inflammation of the urinary bladder and associated structures associated with venereal disease, irritation by a foreign body, injury, and radiation therapy for cancers of the pelvic region. Malignancy associated cystitis includes, but is not limited to, inflammation of the urinary bladder and associated structures associated with cancerous growth. Undetermined causes of cystitis include, but are not limited to, inflammation of the urinary bladder and associated with interstitial cystitis. Other causes of cystitis are known to those skilled in the art and are included as cystitis.
It has been suggested that abnormalities of or deficiencies in the glycosaminoglycan layer lining the transitional epithelium of the urinary bladder may be a primary defect in cystitis. (Eldrup J. 1983. British Journal of Urology, 55:488). These abnormalities or deficiencies may enable increased permeability of the transitional epithelium (Parsons, E. L. et al. 1990. Journal of Urology, 143:690) and this increased permeability may enable urinary solutes to gain access to the subepithelial tissue and to induce an irritative, inflammatory response that contributes to the symptoms of cystitis.
There is no standard treatment for cystitis. Among the treatments used for interstitial cystitis are hydraulic distention of the urinary bladder, oral amitriptyline or sodium pentosanpolysulfate, intravesical instillation of dimethylsulfoxide, oxychlorosene sodium, silver nitrate, heparin, or a composition comprising an angiostatic steroid and pentosanpolysulfate. However, the efficacy of these treatments is variable.
Hydraulic distention of the urinary bladder is done under general or spinal anesthesia for one to two minutes at a pressure of 80 to 100 cm H.sub.2 O. In one study using hydraulic distention of the urinary bladder to treat interstitial cystitis, less than 55% of the patients treated reported relief immediately after treatment and only 2% reported relief six months after treatment (Hanno P. M. et al. 1991. Semen Urology,9:143)
Instillation of dimethylsulfoxide (DMSO) into the urinary bladder for six to eight weeks resulted in a 53% response rate to DMSO versus an 18% response rate to placebo, with the average length of response being six months (Perez-Marrero, R. et al. 1967. Journal of Urology, 98:671). Pharmacological effects of DMSO include membrane penetration, enhanced drug absorption, anti-inflammatory and analgesic effects, collagen dissolution, muscle relaxation and mast cell histamine release. Side effects include increased vesicle irritability and garlic-like breath odor. Equivalent results to instillation of DMSO have been reported with oxychlorosene sodium (Messing, E. M. et al. 1978. Urology, 12:381). However instillation of oxychlorosene sodium requires anesthesia because of intense discomfort.
Sodium pentosanpolysulfate is a low molecular weight synthetic glycosaminoglycan (U.S. Pat. No. 4,524,066 to Wolf) characterized by very low viscosity and high electronegativity. U.S. Pat. No. 4,820,693 to Gillespie (Gillespie '693) discloses a composition and method for arresting angiogenesis and cell, capillary or membrane leakage comprising either oral or intravesical administration of an angiostatic steroid and pentosanpolysulfate. The molecular weight of pentosanpolysulfate is between 1.5.times.10.sup.3 and 5.times.10.sup.3 Daltons (The Merck Index, 11th Edition. 1989. p. 7093 at 7090). The molecular weight of the pentosanpolysulfate claimed in Gillespie '693 is between 1.6.times.10.sup.3 and 6.times.10.sup.3 Daltons, and is preferably about 2.times.10.sup.3 Daltons. U.S. Pat. No. 4,966,890 to Gillespie (Gillespie '890) discloses a composition and method for treating cystitis comprising either oral or intravesical administration of an angiostatic steroid and pentosanpolysulfate. Gillespie '890 teaches that pentosanpolysulfate can be used in place of heparin and that pentosanpolysulfate, in combination with an angiostatic steroid, cures cystitis by arresting angiogenesis, cell membrane leakage and capillary leakage or exchange in the urinary bladder.
U.S. Pat. No. 5,180,715 to Parsons (Parsons '715) also discloses the use of pentosanpolysulfate for treating cystitis. Parsons '715 provides data to show that oral pentosanpolysulfate at doses in excess of 100 mg per day are most effective for treating cystitis. Parsons '715 teaches that pentosanpolysulfate can be used in place of heparin and that pentosanpolysulfate acts to block bacterial adherence to the transitional epithelium of the urinary bladder.
Pentosanpolysulfate, as disclosed in Gillespie '693, in Gillespie '890 and in Parsons '715, is a low viscosity glycosaminoglycan. As cystitis may be related to a defect in the high viscosity glycosaminoglycan layer on the luminal surface of the urinary bladder, intravesical administration of the low viscosity pentosanpolysulfate does not provide adequate protection to the transitional epithelium of the urinary bladder and associated structures. Therefore, what is needed is a method for the treatment of cystitis that provides adequate protection for the transitional epithelium of the urinary bladder and related structures with minimal adverse side effects.